Hyperuricemia and dementia - a case-control study.

BACKGROUND: There is evidence that uric acid may have antioxidant and neuroprotective effects and might therefore alter the risk for neurodegenerative diseases such as dementia. So far, the relation between serum uric acid (SUA) levels or hyperuricemia and dementia remains elusive. Most studies focused on the disease or SUA levels. Effects of anti-hyperuricemic treatment have not been considered yet. This study investigated the association between hyperuricemia and dementia taking into account anti-hyperuricemic treatment. METHODS: We used longitudinal German public health insurance data and analyzed the association between hyperuricemia with and without different treatment options and dementia in a case-control design. Applying logistic regression the analysis was adjusted for several potential confounders including various comorbidities and polypharmacy. RESULTS: We identified 27,528 cases and 110,112 matched controls of which 22% had a diagnosis of hyperuricemia or gout and 17% received anti-hyperuricemic drugs. For patients with a diagnosis of hyperuricemia we found a slightly reduced risk for dementia (adjusted odds ratio [OR] 0.94, 95% confidence interval [CI] 0.89 to 0.98). The risk reduction was more pronounced for patients treated with anti-hyperuricemic drugs (adjusted OR 0.89, 95% CI 0.85 to 0.94, for regular treatment). CONCLUSIONS: Our results showed a slight reduction for dementia risk in patients with hyperuricemia, both with and without anti-hyperuricemic treatment.

Discriminatory power of standard toxicity assays used to evaluate ingredients added to cigarettes.

A tiered approach for testing ingredients in a cigarette matrix was developed and includes chemical-analytical testing and a standard battery of biological toxicity assays. These assays were adapted for comparative evaluation of mainstream smoke from experimental cigarettes with or without ingredients at various inclusion levels. This adaptation to test cigarette mainstream smoke may impact assay response. Since it is difficult to a priori determine discriminatory power, it was evaluated using a large experimental dataset from a multi-year program of cigarette ingredient testing performed at two separate laboratories. A statistical method, minimum detectable difference (MDD), was used as a measure of assay discriminatory power. MDD of cigarette smoke constituents ranged from 6% to 29% of the average. Salmonella mutagenicity and cytotoxicity test MDDs ranged from 20% to 81% and 18% to 49%, respectively. Body weight gain in 90-day nose-only inhalation studies yielded an MDD of 30-40%. Histopathological findings with severity scores between 0.5 and 1.5 had the lowest MDDs of 23% and higher. In general, discriminatory power decreased with increasing biological complexity and toxicological relevance of the assay. Beyond statistical analysis, however, a weight-of-the-evidence analysis by experienced researchers is required for toxicological assessment of a cigarette ingredient.

N-Nitrosodimethylamine-Contaminated Valsartan and the Risk of Cancer­A Longitudinal Cohort Study Based on German Health Insurance Data.

BACKGROUND: N-Nitrosodimethylamine (NDMA), classified as a probable human carcinogen, has been found as a contaminant in the antihypertensive drug valsartan. Potentially carcinogenic effects associated with the consumption of NDMAcontaminated valsartan have not yet been analyzed in large-scale cohort studies. We therefore carried out the study reported here to explore the association between NDMA-contaminated valsartan and the risk of cancer. METHODS: This cohort study was based on longitudinal routine data obtained from a large German statutory health insurance provider serving approximately 25 million insurees. The cohort comprised patients who had filled a prescription for valsartan in the period 2012-2017. The endpoint was an incident diagnosis of cancer. Hazard ratios (HR) for cancer in general and for certain specific types of cancer were calculated by means of Cox regression models with time-dependent variables and adjustment for potential confounders. RESULTS: A total of 780 871 persons who had filled a prescription for valsartan between 2012 and 2017 were included in the study. There was no association between exposure to NDMA-contaminated valsartan and the overall risk of cancer. A statistically significant association was found, however, between exposure to NDMA-contaminated valsartan and hepatic cancer (adjusted HR 1.16; 95% confidence interval [1.03; 1.31]). CONCLUSION: These findings suggest that the consumption of NDMA-contaminated valsartan is associated with a slightly increased risk of hepatic cancer; no association was found with the risk of cancer overall. Close observation of the potential long-term effects of NDMA-contaminated valsartan seems advisable.

Glucocorticoid Therapy is Associated with a Lower Risk of Dementia.

BACKGROUND: Recent evidence indicates an important role for neuroinflammation in the pathological cascade of Alzheimer's disease (AD), and neuroinflammation is increasingly being recognized as a potential therapeutic target. OBJECTIVE: To assess the impact of glucocorticoids on the risk of developing dementia. METHODS: We used health insurance data of the largest German health insurer from 2004-2013 with a baseline sample of 176,485 persons aged 50 years and older to study the association of glucocorticoid treatment and incidence of dementia. Cox proportional-hazard models were calculated adjusting for sex, age, and comorbidities known to be major risk factors for dementia and were given as hazard ratios (HR) with 95% confidence intervals (CI). We further stratified glucocorticoid treatment by route of application and treatment duration. RESULTS: Of the 176,485 dementia-free persons, 19,938 were diagnosed with dementia by the end of 2013. The risk of suffering from dementia was significantly lower for glucocorticoid users compared to non-users (HR = 0.81, CI = 0.78-0.84). The lowest risk was found among users of inhaled glucocorticoid (HR = 0.65, CI = 0.57-0.75), followed by nasal (HR = 0.76, CI = 0.66-0.87), other (HR = 0.84, CI = 0.80-0.88), and oral users (HR = 0.83, CI = 0.78-0.88). We found no difference in risk reduction between long- and short-term-users. CONCLUSION: Longitudinal German health insurance data indicate that the use of glucocorticoids is associated with a lower risk of dementia. Prospective clinical trials will be necessary to determine whether glucocorticoids can have a positive impact on neuroinflammation and thus protect persons against dementia.

Influence of metabolic profiles on the safety of drug therapy in routine care in Germany: protocol of the cohort study EMPAR.

INTRODUCTION: Pre-emptive testing of pharmacogenetically relevant single-nucleotide polymorphisms can be an effective tool in the prevention of adverse drug reactions and therapy resistance. However, most of the tests are not used as standard in routine care in Germany because of lacking evidence for the clinical and economical benefit and their impact on the usage of healthcare services. We address this issue by investigating the influence of pharmacogenetic profiles on the use of healthcare services over an extended period of several years using routine care data from a statutory health insurance company. The goal is to provide clinical evidence whether pre-emptive pharmacogenetic testing of metabolic profiles in routine care in Germany is beneficial and cost-effective. METHODS AND ANALYSIS: The EMPAR (Einfluss metabolischer Profile auf die Arzneimitteltherapiesicherheit in der Routineversorgung) study is a non-interventional cohort study conducted to analyse pharmacogenetic risk factors that are important for drug therapy by means of endpoints relevant for healthcare. The analysis is based on pharmacogenetic profiles and statutory health insurance data. We perform pharmacogenetic, pharmacoepidemiological and pharmacoeconomic analyses using health care utilisation scores and machine learning techniques. Therefore, we aim to include about 10 000 patients (≥18 years) insured by the health insurance provider Techniker Krankenkasse. The study focuses on patients with prescriptions of anticoagulants and prescriptions of cholesterol-lowering drugs. Also, a screening for special pharmacogenetic characteristics will be performed in patients with at least one Y57.9! diagnosis (Complication of medical and surgical care: drug or medicament, unspecified). Outcomes include the utilisation of health insurance services, the incidence of incapacity for work and costs for drugs and treatment. ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committee of the Medical Faculty, University of Bonn (Lfd. Nr. 339/17). The results of this research project will be published in scientific open access journals and at conferences. TRIAL REGISTRATION NUMBER: German Clinical Trials Register, DRKS00013909.

Evaluation of the micronucleus assay in bone marrow and peripheral blood of rats for the determination of cigarette mainstream-smoke activity.

The mammalian in vivo micronucleus assay is widely used as part of the genotoxicity testing battery required during the development of new drugs. As such, the in vivo micronucleus assay has been used in a battery of assays for the assessment of cigarette ingredients or design modifications to help ensure that there is no increase in risk or any new risk introduced by these additions or modifications. The present series of studies was conducted to optimize and evaluate this assay for the assessment of the effects of mainstream smoke on the micronucleus frequency in the bone marrow and peripheral blood of rats. In a first experiment, the optimal conditions for performing the micronucleus assay in these tissues were determined. This was done by use of two compounds known for their micronucleus-inducing activity, i.e., the clastogen cyclophosphamide and the aneugen colchicine. In a second experiment, the effects of tube restraint on untreated control rats were investigated. In a third experiment, the optimal conditions were used to assess the clastogenic/aneugenic activity of cigarette smoke in Sprague-Dawley rats. The rat micronucleus assay in both bone marrow and peripheral blood is able to detect clastogenic and aneugenic activity. The flow cytometric determination of micronucleated cells in rat blood is at least as sensitive as determinations in bone marrow. No statistically significant differences were observed in micronucleus frequencies between rats with and without the additional stress of tube restraint; however, the cautious approach would be to use a fresh-air-exposed group (with tube restraint) as the negative control in inhalation experiments. Using the conditions identified as optimal in the above-mentioned experiments, the micronucleus assay was not able to detect effects induced by smoke from conventional cigarettes. Nevertheless, the micronucleus assay will remain a valuable tool as part of a testing battery used to investigate possible adverse effects related to product modifications.

Toxicological comparisons of three styles of a commercial U.S. cigarette (Marlboro with the 1R4F reference cigarette.

Toxicological comparisons were made of three commercial cigarettes, namely Marlboro full flavor, Marlboro Lights, and Marlboro Ultra Lights, with the 1R4F reference cigarette. The main comparison was a 90-d inhalation study with mainstream smoke at 150 mg total particulate matter per cubic meter, in Sprague-Dawley rats using 6 h/d and 7 d/w exposures. The principal endpoint was histopathology of the respiratory tract, along with examinations of free lung cell counts after broncho-alveolar lavage. Additional studies on mainstream smoke included Salmonella mutagenicity, cytotoxicity of particulate and gas/vapor phases, and analytical chemistry. The exposures produced effectively the same responses in each of the four groups, and the histopathology results in the commercial cigarette groups were also effectively the same. The 1R4F was also tested at 75 and 200 mg/m(3), and most of the histopathology results obtained here showed dose-response relationships. The free lung cell responses were similar in the 1R4F/commercial cigarette comparison, and there were dose-related changes in the 1R4F groups, most notably for neutrophils. Most of the changes produced in the 90-d of exposure were resolved in a 42-d post-inhalation period. Responses in the in vitro and analytical assays for the four cigarettes were in general similar, when data were expressed either per mg TPM or per mg tar yield. There were judged to be no toxicologically meaningful differences between the profiles evaluated at similar smoke concentrations for the three commercial cigarettes and for the 1R4F using these assays.

Use of Antiepileptic Drugs and Dementia Risk-an Analysis of Finnish Health Register and German Health Insurance Data.

OBJECTIVES: To evaluate the association between regular antiepileptic drug (AED) use and incident dementia. DESIGN: Case-control analysis. SETTING: Finnish public health register and German health insurance data. PARTICIPANTS: Individuals with dementia of any type (German data, N=20,325) and Alzheimer's disease (AD; Finnish data, N=70,718) were matched with up to four control persons without dementia. MEASUREMENTS: We analyzed the association between regular AED use and dementia. To address potential protopathic bias, a lag time of 2 years between AED use and dementia diagnosis was introduced. Odds ratios (ORs) were calculated by applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. RESULTS: Regular AED use was more frequent in individuals with dementia than controls. Regular use of AEDs was associated with a significantly greater risk of incident dementia (adjusted OR=1.28, 95% confidence interval (CI)=1.14-1.44) and AD (adjusted OR=1.15, 95% CI=1.09-1.22) than no AED use. We also detected a trend toward greater risk of dementia with higher exposure. When AEDs with and without known cognitive adverse effects (CAEs) were compared, a significantly greater risk of dementia was observed for substances with known CAEs (dementia: OR=1.59, 95% CI=1.36-1.86; AD: OR=1.19, 95% CI=1.11-1.27). CONCLUSION: AEDs, especially those with known CAEs, may contribute to incident dementia and AD in older persons.

Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis.

IMPORTANCE: Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline. OBJECTIVE: To examine the association between the use of PPIs and the risk of incident dementia in the elderly. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015. EXPOSURES: Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole. MAIN OUTCOMES AND MEASURES: The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy. RESULTS: A total of 73,679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70,729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001). CONCLUSIONS AND RELEVANCE: The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of ß-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.

Regular Benzodiazepine and Z-Substance Use and Risk of Dementia: An Analysis of German Claims Data.

BACKGROUND: While acute detrimental effects of benzodiazepine (BDZ), and BDZ and related z-substance (BDZR) use on cognition and memory are known, the association of BDZR use and risk of dementia in the elderly is controversially discussed. Previous studies on cohort or claims data mostly show an increased risk for dementia with the use of BDZs or BDZRs. For Germany, analyses on large population-based data sets are missing. OBJECTIVE: To evaluate the association between regular BDZR use and incident any dementia in a large German claims data set. METHODS: Using longitudinal German public health insurance data from 2004 to 2011 we analyzed the association between regular BDZR use (versus no BDZR use) and incident dementia in a case-control design. We examined patient samples aged≥60 years that were free of dementia at baseline. To address potential protopathic bias we introduced a lag time between BDZR prescription and dementia diagnosis. Odds ratios were calculated applying conditional logistic regression, adjusted for potential confounding factors such as comorbidities and polypharmacy. RESULTS: The regular use of BDZRs was associated with a significant increased risk of incident dementia for patients aged≥60 years (adjusted odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13-1.29). The association was slightly stronger for long-acting substances than for short-acting ones. A trend for increased risk for dementia with higher exposure was observed. CONCLUSION: The restricted use of BDZRs may contribute to dementia prevention in the elderly.